Iodine-containing amino-benzoyl derivatives of amino acids



Patented June 1, 1954 IODINE-CONTAINING AMINO-BENZOYL DERIVATIVES F AMINO ACIDS Vernon H. Wallingford, Ferguson,

Mo., assignor to Mallinckrodt Chemical Works, St. Louis, Mo., a corporation of Missouri No Drawing. Application August 24, 1951, Serial No. 243,577

8 Claims. 1

This invention relates to iodine-containing amino-benzoyl derivatives of amino acids and more particularly to 3-amino-2,4,6'-triiodo derivatives of benzoyl amino acid compounds and to methods for their preparation.

This application is a continuation-in-part of my copending application Serial No. 94,253, filed May 19, 1949, now abandoned.

Briefly the invention comprises methods of making certain compounds of a group having the formula:

where R is selected from the group consisting of methylene, and polymethylene radicals, and R is selected from the group consisting of alkyl and phenyl radicals and hydrogen, by reducing a m-nitro-benzoyl derivative of an amino acid with zinc and hydrochloric acid and thereafter iodinating the benzoyl nucleus with iodine monochloride. The present invention also includes new compounds of the type described above, as well as methods for reducing the nitro group of a nitro-benzoyl derivative of an amino acid with zinc and hydrochloric acid.

Among the objects of this invention are the provision of new compounds which are 3-amino- 2,4,6-triiodobenzoyl derivatives of amino acids; the provision of compounds of the type indicated which are useful intermediates for the preparation of other compounds of related structure; the provision of compounds of the type referred to which possess relatively low toxicity toward human bodies; the provision of compounds of the type referred to which possess substantial solubility in water; the provision of improved contrast media for X-ray diagnosis; the provision of compounds which are relatively stable under normal conditions of storage and use and in the presence of body fluids, and the provision of methods for preparing compounds of the type referred to. Other features will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.

Because of the opacity of iodine to X-rays, many iodinated organic compounds have been proposed as X-ray contrast agents; but only a few of these are now recognized as being of any praca tical value. The problem remains of providing a high degree of contrast for X-ray diagnosis with greater safety and comfort to the patient. This can be achieved, for example, by providing contrast agents that are (1) less toxic, so that larger amounts can be given to the patient; (2) more soluble, so that greater concentrations of the contrast agent are possible; or (3) more opaque to X-rays because of a greater proportion of iodine but without a corresponding increase in toxicity.

Iodinated derivatives of benzoic acid are among those compounds that have been proposed as X-ray contrast agents. Although they appear to be promising X-ray contrast agents because of the large amount of iodine that they contain, the toxicity or the insolubility of the known derivatives of these compounds have generally been found to be too great for this purpose.

It has been found in accordance with the present invention that the properties required in a good X-ray contrast agent are obtained in certain compounds of the type:

where R represents a methylene, substituted methylene, polymethylene, or substituted polymethylene residue, the substituents being alkyl and phenyl radicals and hydrogen, and the nontoxic salts thereof.

An outstanding property of these new compounds is the remarkably greater solubility of certain of their salts compared with the solubility of the corresponding salts of the simple polyiodinated aminobenzoic acids. This is particularly true of the salts of the alkali metals, ammonia and amines. Another equally valuable property of many of these compounds is their substantially lower toxicity as compared with the corresponding olyiodinated aminobenzoic acids.

These compounds can be prepared by converting a polyiodinated m-aminobenzoic acid to the acid chloride and coupling the product with an amino acid. Alternatively, to prepare m-amino hippuric acid, for example, m-nitro-benzoic acid may be coupled with aminoacetic acid and the resulting nitro compound reduced with ammonium sulfide and finally iodinated.

It has been found in accordance with the present invention, however, that these compounds are most advantageously prepared by first reducing the m-nitro-benzoyl derivative of an amino acid with zinc and hydrochloric acid, and then iodinating the benzoyl nucleus with iodine monochloride without first isolating the amine derivative. The action of zinc and hydrochloric acid is a surprising feature of this process because they have not heretofore been regarded by the art "as general reactants for the reduction of nitroaromatic compounds.

There are many amino acids that can be used in preparing the compounds of this invention. In addition to the common amino aliphatic acids, phenyl-suibstituted amino carboxylic acids may be employed, provided the amino group itself is attached to an aliphatic carbon atom. In general, this reaction has not been found suitable for amino acids that contain more than one nitrogen atom.

The following examples illustrate the invention:

EXAMPLE 1 3-amino-2,4,6-trii0dohipparic acid Meta-nitrobenzoyl chloride (28.3 g.) was added slowly with stirring to aminoacetic acid g.) and water (50 m1.), while the mixture was kept slightly alkaline to phenolphthalein with sodium hydroxide solution (35 B.) and the temperature was maintained at about C. Addition of the chloride required about minutes and a total of 27 ml. of the sodium hydroxide solution was used. Stirring was continued for about one hour after all of the chloride was added.

The resulting clear and slightly yellowish solution was transferred to a separatory funnel and gradually added over a period of 30 minutes to a stirred mixture of zinc dust (10 g.) and water (75 m1.) while the mixture was kept acid to Congo red with concentrated hydrochloric acid. Two additional 10 g. portions of zinc dust were added. After the reduction was apparently complete, fresh zinc dust (5 g.) was added and the mixture was heated and stirred to insure complete reduction. Altogether, 105 ml. of concentrated hydrochloric acid and 35 g. of zinc dust were used. The excess zinc was filtered off and the resulting clear and colorless solution was diluted to about 2000 ml. To it was added a mixture of iodine monochloride (60 g.) and concentrated hydrochloric acid (60 ml). Since the reaction was not rapid, the solution was heated on a steam bath for about one hour at -60 C. A tan product separated which, after filtering and drying, weighed 50 g. It was evidently a mixture of diand triiodo compounds because attempts to purify it by crystallization as the ammonium salt gave fractions melting from 150 C. to 211 C. This crude iodinated product was dissolved in water (700 ml.) with the aid of sodium hydroxide and precipitated with hydrochloric acid. The precipitate was heated on a steam bath with iodine monochloride (25 g.) in concentrated hydrochloric acid (25 ml.) for one hour at C. During that time the material changed to a more dense, brownish solid, but the weight remained 50 g. It was recrystallized from water (500 ml.) containing ammonium chloride (100 g.) and ammonium hydroxide (13 ml.) by heating the solution to a maximum temperature of about C., and then cooling it in an ice bath. The arm monium salt which crystallized out was filtered off and Washed with two 25 ml. portions of ammonium chloride solution (20 g. in ml. of water) and dissolved in hot water (500 ml.) containing a few drops of ammonium hydroxide. This solution was heated with activated carbon, filtered and then 3-a-mino-2,4,6-triiodohippuric acid was precipitated from the hot solution with acetic acid (10 ml). After it was washed and dried the acid weighed 46.7 g. It melted at 230 C. with decomposition when it was placed in the melting point apparatus at 215 C. and the temperature was increased at the rate of 3 per minute.

The mother liquor, from which the original crude iodinated product was obtained, was treated with additional iodine monochloride (30 g.) in concentrated hydrochloric acid (30 ml.) for two hours at 60 C. From this an additional 20 g. of crude iodinated product was obtained. After it had been purified through the ammonium salt, it weighed 15.5 g. and melted at 225 C. with decomposition.

The combined yield of purified product was 62.2 g. (74.4% of theory based on meta-nitrobenzoyl chloride). The 3-amino-2,-i,6-triiodohippuric acid was not completely colorless but retained a slight tan cast. Analysis showed 65.9 and 66.1% iodine, compared with 66.5% which is theory for C9H7OsN2I3. The neutralization equivalent was found to be 569.3. Theory is 571.7.

EXANIPLE 2 Sodium salt of 3-amino-2,4,6-triiodohippuric acid A suspension of purified 3 -amino-2,4,6-triiodohippuric acid (10 g.) in water (30 ml.) was made slightly alkaline to litmus with sodium hydroxide and the resulting reddish solution was evaporated under reduced pressure. Light tan crystals resulted. The solubility of the sodium salt of 3- amino-2,4,6-triiodohippuric acid was 10 g. in 23.5 ml. of water at 28 C.

EXANIPLE 3 Diethanolamine salt of 3amino-2,4,6-triiodohippuric acid A suspension of free 3-amino-2,4,6-triiodohippuric acid (10 g.) in water (25 ml.) was neutralized with diethanolamine (2.5 ml.) and then evaporated under reduced pressure. The resulting diethanolamine salt of S-amino-ZAfi-triiodohippuric acid could not be crystallized but was obtained as a clear, reddish, glassy solid. It was extremely soluble in water.

EXAIVEPLE 4 N-(3-amino-2,4,6-triiodobenzoyl) -e-aminoncaproz'c acid e-caprolactam (34 g., 6.3 mole) was hydrolyzed by refluxing it with a solution of sodium hydroxide (25.6 g. in 25.6 ml. of water until 15 minutes after the mixture became homogenous. To onehalf of this mixture, hydrochloric acid (3 ml.) was added to neutralize the excess sodium hydroxide, and then m-nitrobenzoyl chloride (37.2 g.) was slowly added with stirring while the mixture was kept just alkaline to phenolp'nthalein with the remaining half of the sodium e-allllnO- caproate. After the mixture stood over a wee end, a few granules of m-nitrobenzoyl chloride still remained, so 35 Be. sodium hydroxide solution (2 ml.) was added and the mixture was stirred for one hour. Even then the chloride failed to dissolve. The supernatant solution was,

therefore, poured 01f and acidified. The nitro compound, which separated as a thick white paste, was collected on a filter and washed.

The nitro compound was reduced by adding portions of it to a stirred mixture of ammonium chloride (42 g.), zinc dust (83.5 g.) and hydrochloric acid (160 ml.). When the reaction appeared to be slowing more hydrochloric acid and zinc dust were added. The temperature finally was raised to about 90 C. for one hour to complete the reaction. The final volume was made up to 3 liters by dilution with water. Additional hydrochloric acid (300 ml.) was then added, followed by iodine monochloride (120 g.) mixed with hydrochloric acid (120 1111.). This mixture was allowed to stand overnight and then stirred for 3 hours at -85 C. The crude iodinated product was in the form of a tar weighing 121.5 g. It was placed in water (400 ml.) containing sodium sulfite (2 g.), B. sodium hydroxide solution (30 ml.) was added and the mixture was warmed to dissolve the tar. After filtering the resulting solution, sodium chloride g.) and 35 B. sodium hydroxide solution (40 ml) were added to it, and it was placed in a refrigerator. The sodium salt, which crystallized overnight, was separated from the mother liquor by centrifugation, washed with a solution (150 ml) having the same composition as the mother liquor (10% sodium chloride plus 10% sodium hydroxide), and again centrifuged. It dissolved readily in water (1200 ml.) and was precipitated first with 1:5 acetic acid and then with hydrochloric acid until the liquid was acid to Congo red. After filtering and washing the precipitate with Water, it was dried to constant weight at 70 C. It weighed 82.2 g. (66% of theory) and melted at 140-144 C. when it was placed in the melting point apparatus at 100 C.

The crude material obtained above was found to be a mixture of the desired product with 3- amino 2,4,6 triiodobenzoic acid. These were separated as follows: The crude material Was dissolved with stirring in water (1600 ml.) that Was kept just alkaline to phenolphthalein with 35 B. sodium hydroxide solution. Crude N-(3- amino-2,4,6-triiodobenzoyl-e-amino n caproic acid was precipitated from the solution with 1:5 acetic acid. The precipitate was filtered, washed, and then dried at'70 C. It weighed 67.2 g. and melted to an orange liquid at 152156 C. The crude product was purified through the sodium salt, dried first in a vacuum desiccator overnight and then to constant weight at 70 C. It weighed 62.8 g. (93% of theory) and melted to a tan liquid at 154-156 C. A sample (2 g.) of this product was further purified by recrystallization from (by volume) ethyl alcohol (40 ml.), after first treating the alcoholic solution with activated carbon. The purified N-(3-amino2,4,6-triiodobenzoyl)-e-arnino-n-caproic acid weighed 1.6 g. (80% recovery) It melted to a light yellow liquid at l58.5-160 C. Found on analysis: 24.45% and 24.48% carbon; 2,55% and 2.38% hydrogen. Calculated for C13H15O3N2I3: 24.84% carbon; 2.41% hydrogen.

The filtrate from the acetic acid precipitation was precipitated first with dilute hydrochloric acid and then with concentrated hydrochloric acid until the liquid was acid to Congo red. The precipitate was filtered, washed, and dried at 70 C. It weighed 14.5 g. and melted at 191 with decomposition. This material was purified and proved to be 3-amino-2,4,6-triiodobenzoic acid.

6. EXAMPLE 5 N- (3-amino-2,4,6-triiodobenzoyl) -oc(lmi'll0 phenylacetic acid M-Nitrobenzoyl chloride (9.3 g.) was added in small portions with stirring to dl-u-aminophenylacetic acid (9.5 g.) and water (25 ml.) while 35 Be. sodium hydroxide solution (15 ml. in all) was added periodically to keep the mixture alkaline to phenolphthalein and the temperature was kept below 30 C. by cooling the reaction vessel in a Water bath. After all of the m-nitrobenzoyl chloride was added and the mixture had been stirred for one hour, a considerable portion of the chloride was still undissolved. It did dissolve to give a clear, bright red solution when stirring was continued overnight. On adjusting the acidity to pH 5 (Hydrion paper) with dilute hydrochloric acid, a yellowish white precipitate formed. This was collected on a filter and dried. It weighed 3.9 g. and melted to a yellow liquid at 208 C. The filtrate was made acid to Congo red with dilute hydrochloric acid. A light red oil separated which later crystallized to a gray-white solid. The solid was filtered, washed, and then crushed in a mortar. It was reduced with zinc dust (15 g.), hydrochloric acid (21 ml.), ammonium chloride (14 g.) and water (69 ml.) using the procedure described in Example 4. The reduction porceeded with unusual ease and rapidity. Although the reaction appeared to be complete after 45 minutes, the mixture was stirred at {30-90 C. for an additional one-half hour. After filtering off the zinc and diluting the filtrate to 400 ml., hydrochloric acid (40 ml.) was added followed by the further addition of a mixture of iodine monochloride (30 g.) in hydrochloric acid (30 ml). The mixture was stirred for two hours at room temperature. During this time a sticky black tar formed which changed to hard lumps on standing overnight. After being removed and ground in a mortar, these lumps were returned to the iodine monochloride mother liquor which was then warmed and stirred for ninety minutes at 5060 C. At this point some of the liquid was lost through accident. The remainder was stirred for an additional hour at (SO-70 C. It was then cooled to 27 C. and bleached with 5 g. of sodium bisulfide. A light, brown-gray solid formed. This was filtered, washed and dried at 66 C. The crude N-(3-amino-2,4,6-triiod0ben zoyl)-a-aminophenylacetic acid weighed 14.7 g. and melted at 190-192 C. with decomposition.

The crude iodinated compound dissolved easily in 50% (by volume) ethyl alcohol, 50% (by volume) isopropyl alcohol, acetic acid, dioxane and 50% (by volume) dioxane, but it did not crystallize from any of these solvents. It was soluble in cold (by volume) butyl alcohol. When warmed with acetic anhydride, it was easily acetylated. The sodium and ammonium salts, when salted out of their solutions, separated as oils.

A portion of the crude material (1 g.) was recrystallized from 45% (by volume) ethyl alcohol (45 ml). Even though the alcoholic solution was treated with activated carbon, the portion of the acid that was recovered (30%) retained a slight pink color. It melted at 223-224 C. There was no esterification as shown by the complete solution of the product in water containing ammonium hydroxide. Found on analysis: 27.45% and 27.14% carbon; 1.96% and 1.99% hydrogen. Calculated for C15H11O3N'2I3: 27.78% carbon; 1.71% hydrogen.

7 EXAMPLE 6 N- (3-amino-2,4,6-triiodobenzoyl) -p-alanine To a stirred, cooled (-35 C.) solution of ,8- alanine (14 g.) in water (63 ml.) was added portionwise a solution of m-nitrobenzoyl chloride (23.4 g.) in dioxane ('7 ml.), maintaining a pH of around 9 throughout the addition by pertionwise addition of B. sodium hydroxide (a total of 30 ml. was required). After the addition was complete, the mixture was stirred for one hour, diluted to 1800 ml., and acidified with glacial acetic acid to pH 5, then with concentrated hydrochloric acid to pH 3. After stirring for thirty minutes, N-(3-nitrobenzoyD-e-alanine, 24 g. (80.6%), M. P. 18l.2182.4 0., was separated by filtration and dried in a vacuum desiccator. Neut. equiv. theory: 238, found: 238.

To a stirred suspension of N(3-nitrohenzoyl) p-alanine (24 g.) and ammonium chloride (21 g.) in water (100 ml.) was added portionwise 23.0 g. of zinc dust at such a rate that the temperature was maintained at Sit-85 C'. by intermittent application of an ice-water bath. The reaction mixture was stirred for one-half hour after all the zinc was added, diluted with concentrated hydrochloric acid (125 m1), and stirred for one hour longer. The resulting pale blue solution was filtered to remove the excess zinc and added to a stirred, heated (70 C.) solution of iodine monochloride g.) and concentrated hydrochloric acid (60 ml.) in water (500 ml). After two and one-half hours stirring at C. sodium bisulfite (16 g.) was added and stirring was continued for one hour. The crud product, a brown fiuffy solid, 50 g. (86%) was separated by filtration and dried in a vacuum desiccator. To a solution of the crude product in water (500 ml.) containing concentrated ammonium hydroxide (13 ml.) was added ammonium chloride an). The precipitated ammonium salt was separated by filtration, washed with 20% ammonium chloride solution, and dissolved in water (1 liter) containing concentrated ammonium hydroxide (1 ml.). The product, N-(3-amino2,4,0-triiodcbenzoyl) -B-alanine, was precipitated by careful acidification with 15% acetic acid, followed by concentrated hydrochloric acid to pH 3. After filtration and drying, the product weighed 43 g. (73.5% over-all yield) and melted at 220- 220.3 C. After two crystallizations from 50% ethanol, the product melted at 223.6-2252" C.

Calcd. for C10H9N2O3I3; C, 20.50; H, 1.55; I, 64.98; neut. equiv., 585.95. Found: C, 20.71, 20.65; H, 1.65, 1.79; I, 64.47, 64.28: neut. equiv. 586.9.

EXAIVIPLE 7 N Gamma-2,4,6 -trz'z'odobeneoyl) -a-am-z'novaleric acid To a stirred mixture of a-aminovaleric acid (100 g.) in water (1 liter) at 35 C. was added portionwise m-nitrobenzoyl chloride g.) dissolved in dioxane (30 ml.) The pH was maintained at approximately 8 by portionwise addition of 35 B. sodium hydroxide. A total of ml. of sodium hydroxide was required. ihe temperature was maintained at 30-35 C. with an ice-water bath. One hour and ten minutes after completion of the addition, the solution was filtered. The filtrate was diluted to 7.5 liters and acidified with glacial acetic acid. A turbid suspension of an oil resulted, which crystallized on storing overnight to a fiufiy, crystalline, pale yellow solid, g. (89%), M. P. l56-l5'7 C.

To a stirred suspension of the above acylation product (50 g.) and ammonium chloride (39.6 g.) in water (212 ml.) was added rapidly portionwise 54.6 g. of zinc dust. The reaction mixture was kept at 80-90" C. during the addition by intermittent application of an ice-water bath. Afte1 stirring for fifteen minutes, concentrated hydrochloric acid (236 ml.) was added cautiously. After stirring for one'hour, the excess zinc was removed by filtration and the filtrate set aside for the next step.

To a stirred, heated (70 C.) solution of iodine monochloride (113 g.) and concentrated hydrochloric acid (113 ml.) in water (950 ml.) was added the solution of the reduction product. Within five minutes a tar began to separate, which after two hours solidified. The mother liquor was siphoned ed and the solid ground in a mortar. Both the mother liquor and the pulverized solid were replaced in the reaction flask and stirring at 70 C. was continued for two hours. Th reaction mixture was allowed to cool to room temperature overnight. Sodium bisulfite (20 g.) was added and the bleached susension stirred for three hours at room temperature. The crude product, 108 g. (105%), was separated by filtration and dried in air.

The crude material dissolved in water (2 liters) containing just enough sodium hydroxide to effect solution was decolorized at 60 C. (with a decolorizing agent such as Darco (3-60) and filtered. This treatment did not significantly lighten the deep red color of the solution. Sodium bisulfite (l g.) was added to the solution,

' followed by careful acidification with concentrated hydrochloric acid to pH 4. Just enough 35 B. sodium hydroxide was added to redissolve the suspended product. The product was reprecipitated by acidification with concentrated hydrochloric acid, separated by filtration, washed with water, and pressed dry on the filter. A solution of the product in water (3 liters) containing 35 B. sodium hydroxide (20 ml.) was decolorized (with a decolorizing agent such as Darco (I -60), filtered and acidified very slowly with vigorous stirring to pH 3 with concentrated hydrochloric acid. The product, N-(3-amino- 2,4,6-triiodobenzoyl)-uaminovaleric acid, was separated by filtration, washed with water and dried in air. It weighed 92 grams (90%) and melted at l96.6-200.6 C. Recrystallization from ethanol (1400 ml.) and water (2500 ml.) afiorded 61.1 g. (59%) of the product, M. P. 2035-2 045 C. The solubility of the sodium salt was found to be 47 g. of sodium salt per 100 m1. of water at 25 C.

Neut. equiv. calcd. for C12Hl3N203I3Z Found: 609.3.

A 500 mg. sample was dissolved in 6% ethanol (8.5 ml.) in chloroform and this solution chromatographed on 100 mesh silicic acid. The first band which was eluted from the column with 6% ethanol in chloroform contained 437 mg. of solid (89%). After recrystallization from ethanolwater it melted at 1936-1996 C.

Calcd. for C12H13N203I32 C, 23.47; H, 2.13; I, 62.01; neut. equiv., 614.0. Found: C, 23.84, 23.56; H, 2.22, 2.22; I, 61.73, 62.01; neut. equiv. 617.5.

EXAMPLE. 8

N 3-amino-2,4,6-triiodobeneoyl) t-amino calerie acid To a stirred, cooled (30-35 C.) solution of 6- aminovaleric acid hydrochloride (42.3 g.) in

a water (2'70 ml.) maintained at pH 9 by portion- 9 wise addition of 35 B. sodium hydroxide was added portionwise a solution of m-nitrobenzoyl chloride (37.1 g.) in dioxane (9.5 m1.). A total of 85 ml. of sodium hydroxide was needed. The

10 vived. Th second figure is the dosage which killed at least 60% of the test animals.

In view of the above, it will be seen that the several objects of the invention are achieved and reaction mixture was stirred for one hour after other advantageous results attained. completion of the addition, filtered, and diluted As many changes could be made in the above to 2500 ml. The pale yellow solution was acidimethods and products Without departing from fied with 15% acetic acid to pH 5, followed by the scope of the invention, it is intended that concentrated hydrochloric acid to Congo red all matter contained in the above description paper. The product, 3-nitr0benz0yl-6-aminoshall be interpreted as illustrative and not in a valeric acid, was separated by filtration and dried ti g sense.

in air. It weighed 49 grams (87.5%) and melted I cla m:

t 13513437 9, 1. A compound selected from the group con.-

The 3-nitrobenzoyl-6-aminovaleric acid (49 g.) st ne of compounds having the r u was suspended in a solution of ammonium chlof ride (38.6 g.) in water (207 ml.) and to the stirred mixture was added portionwise 53.3 g. of zinc dust at such a rate that the temperature was maintained at 8085 C. by intermittent application of an ice-water bath. Stirring was continued for one-half hour after completion of the I addition of the Zinc and concentrated hydro where R is selected from the group consisting of chloric acid (230 ml.) was added. After stirring methylene and Polymethylene radicals, and for one hour, the excess zinc was removed from is Selected from the group consisting of alkyl fi the reaction mixture by filtration and the filtrate phenyl radicals and hydrogen and the nontoxlc employed in the iodination. Salts therefJf- To the solution of the above reaction product 3"ammo'z4i64modohlppqilc acid was added a mixture of iodine monochloride (36 a i; 5322 2 ('1- 2,4,6 t llodobenzoyl) e g.) in concentrated hydrochloric acid (36 ml). After storing overnight, this solution of the The nontoxw'salts f (3-an mo-2.4,6-tnmonoiodide was added dropwise to a stirred heatlodobenzoyl) i fi acld' ed (70 0.) solution of iodine monochloride (74.6 f g 2,4,6 tmodobenml) a g.) and concentrated hydrochloric acid (74.6 ml.) in water (920 ml.). The crude product separated Nontoxlc Salts. of N aimmo trk as a tan granular solid. After stirring for three lodobenzoyl) 'a'ammovaleljlc acld: hours, sodium bisulfite (20 g.) was added, and 1 m 0f .makmg amm'bfmmyl stirring was continued for two hours. The crude tlvatlves ammo aclds Whlch c?n lpnses reducproduct, a light tan precipitate, was soluble in mg compound hmmg the formu dilute sodium hydroxide and ammonium hydrox- 40 (EO NH R COOH ide and could not be salted out by the usual methods. A solution of the product in dilute sodium hydroxide Was treated with a decoloriz- No ing agent such as Norit SG, filtered, and acidified with 15% a eti acid, followed by c in which R is selected from the group consisting Waited hydrochlorlc acld to Congo red F of methylene and polymethylene radicals, and R solid was filtered off and recrystallized twice is se1ected from the group consisting of alkyl and from ethanol to yield 60 g. (53%) of pure N-(3- phenyl radicals and hydrogen, t Zinc and amino-2,4,6-triiodobenzoy1)-6-aminovaleric acid, drochloric acid, and thereafter iodinating the melting t The Solubility of the benzoyl nucleons of the resulting amino-benzoyl sodium salt was found to be 89 g. of sodium salt derivative of an amino acid by reaction with per 100 ml. of water at 25 C. iodine monoch1oride Calcdfor C12H13N2O3I2; 2- 3; 8. The method of making amino-benzoyl deneutq Found! C, 1, 4-0 rivatives of amino acids which comprises reduc- H, 2.61, 2.52; I, 61.80, 61.42; neut. equiv. 614.9. 55 ing a, compound having the formula;

The advantageous solubilities and low toxicities CO-NH .R COOH of these new compounds are illustrated by a comparison of the properties of 3-amino-2,4,6triiodohippuric acid and 3-amino-2,4,6-triiodobenzoic acid. 0 N0? solubiliggtgillm ml. Toxic dose Salt usedin et a o m Toxicity Tests Na salt amine salt mgjlnlo gpglrn 3-amlno-2,4,6-trlio- 9.3 24.6 1, 000-1, 500 5 Dlethanolamlne.

dobenzolc acid... 3-amino-2,4,6-triio- 41.5 v. sol. 1, 000-1, 500 3 Sodium.

dohlppuric acid.

In the above the toxicities were determined by in which R is selected from the group consisting injecting aqueous solutions of the salts intraof methylene and polymethylene radicals and R venously into white rats. The first figure is the is selected from the group consisting of alkyl and dosage in milligrams per kilogram of body weight phenyl radicals and hydrogen, with zinc and hyat which at least of the test animals surdrochloric acid, and thereafter adding iodine monochloride to the resulting reaction mixture to iodinat the benzoyl nucleus of the aminebenzoyl amino acid present in said reaction mixture.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date Sachs Nov. 1, 1938 Dohrn et a1. May 30, 1939 Weisblat et a1. Oct. 9, 1951 Archer Oct, 16, 1951 Wallingford Mar. 4, 1952 Wallingford Sept. 23, 1952 12 FOREIGN PATENTS Number Country Date 514,103 Great Britain Oct. 31, 1939 5 OTHER REFERENCES Goldberg et a1, Chem. Abstracts, Vol. 41, col. 4131 (1947).

Houben, Die Methoden der Org. Chem, 3rd

10 ed.., Vol, 2, pp.462-4 (1943) Engler et a1, Schwanert, Beilstein (Handbuch, 4th ed.) vol. 14, p. 390 (1931).

Houben, Die Methoden der Org Chem. (3rd ed.) v01. 2, pp. 381-3 (1943). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 